Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Mol Syst Biol. 2024 Feb;20(2):120-139. doi: 10.1038/s44320-023-00009-2. Epub 2024 Jan 5.
Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.
蛋白质周转率的高效对于细胞内稳态和器官功能至关重要。蛋白质稳态的丧失是衰老的标志，最终导致蛋白质周转率的严重功能障碍。为了研究蛋白质周转率作为年龄的函数的动态变化，我们沿着衰老的连续体对小鼠进行了连续的体内代谢稳定同位素标记。首先，我们发现与心脏和肝脏组织相比，大脑蛋白质组在衰老过程中独特地经历动态周转率波动。其次，大脑蛋白质组在衰老过程中的蛋白质周转率趋势显示出与细胞区室紧密相关的性别特异性差异。接下来，对不溶性蛋白质组的平行分析表明，几个细胞区室的周转率受到阻碍，部分原因是错误折叠。最后，我们发现与年龄相关的蛋白酶体活性波动与核心蛋白水解亚基的周转率有关，这可以通过蛋白酶体活性的药理学抑制来重现。总之，我们的研究提供了蛋白质组范围内跨越衰老连续体的蛋白质周转率图谱，并揭示了单个蛋白酶体亚基的周转率与与年龄相关的蛋白酶体活性下降之间的联系。
